US4446137A - Cephalosporin derivative and pharmaceutical composition containing the derivative - Google Patents

Cephalosporin derivative and pharmaceutical composition containing the derivative Download PDF

Info

Publication number
US4446137A
US4446137A US06/419,076 US41907682A US4446137A US 4446137 A US4446137 A US 4446137A US 41907682 A US41907682 A US 41907682A US 4446137 A US4446137 A US 4446137A
Authority
US
United States
Prior art keywords
derivative
cephalosporin
acetamido
thienyl
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US06/419,076
Other languages
English (en)
Inventor
Shigeaki Muto
Kouichi Niimura
Takao Ando
Masahiko Fujii
Takao Furusho
Chikao Yoshikumi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kureha Corp
Original Assignee
Kureha Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kureha Corp filed Critical Kureha Corp
Assigned to KUREHA KAGAKU KOGYO KABUSHIKI KAISHA, 9-11 HORIDOME-CHO, 1-CHOME, NIHONBASHI, CHUO-KU, TOKYO, JAPAN reassignment KUREHA KAGAKU KOGYO KABUSHIKI KAISHA, 9-11 HORIDOME-CHO, 1-CHOME, NIHONBASHI, CHUO-KU, TOKYO, JAPAN ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ANDO, TAKAO, FUJII, MASAHIKO, FURUSHO, TAKAO, MUTO, SHIGEAKI, NIIMURA, KOUICHI, YOSHIKUMI, CHIKAO
Application granted granted Critical
Publication of US4446137A publication Critical patent/US4446137A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a compound derived from a cephalosporin and a pharmaceutical composition containing the compound as an active ingredient.
  • the invention relates to a compound obtained by modifying chemically a cephalosporin which is one of antibiotics, an antibacterial activity of the compound being lost by such a chemical modification but recovered when the compound is absorbed into a living body, and to a pharmaceutical composition containing the compound as an active ingredient and exhibiting an activity similar to a cephalosporin in a living body.
  • cephalosporin antibiotic An antibiotic which is so-called cephalosporin (hereinafter referred to as a cephalosporin antibiotic) are well known as an excellent drug due to its selective toxicity to bacteria.
  • a cephalosporin antibiotic has a serious defect, that is, it may disturb the beneficial bacterial colonies ordinarily present in living bodies, particularly the intestinal bacterial colonies, since it may also be antibacterially active against the beneficial bacteria. This defect is very serious when such a cephalosporin antibiotic is orally administered.
  • "microbisme selectionne et substitute” is caused resulting in colitis and diarrhea.
  • An object of the invention is to provide an antibiotic which does not have such a defect.
  • An another object of the invention is to provide a compound derived from a cephalosporin antibiotic (hereinafter referred to as a cephalosporin derivative).
  • a still another object of the invention is to provide a pharmaceutical exhibiting an activity similar to a cephalosporin antibiotic in a living body.
  • the cephalosporin derivative of the invention has the general formula (I); ##STR3## wherein R' is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkali metal and R is --CH 2 COOR', --CH 2 CH 2 SR', ##STR4## or --CH 2 CH 2 COOR' wherein R' is defined above.
  • the carboxyl and the thiol groups of the cephalosporin derivative may be in the form of a salt or an thioalcoholate other than alkali metal salt, for example, an alkali earth metal salt, an aluminium salt, an ammonium salt, and the like.
  • the cephalosporin derivative of the invention may be derived from a cephalosporin antibiotic by a chemical modification.
  • the cephalosporin derivative is absorbed into a living body without affecting the bacterial colonies ordinarily present in living bodies and shows an antibacterial activity only when entering into blood in the living bodies, therefore, the cephalosporin derivative of the invention is an antibiotic of the new type quite different from the conventional cephalosporin antibiotics.
  • the cephalosporin derivative of the invention may be prepared by the following process.
  • an amine compound having the general formula (III); ##STR6## wherein R' and R are defined above is added and the reaction is carried out at the temperature of -30° C. to 50° C. for 0.5 to 48 hours.
  • the cephalosporin derivative of the invention is thereafter collected by the conventional method, for example, washing with a solvent, extraction with a solvent, recrystallization, and the like.
  • the cephalosporin derivative of the invention has low toxicity and exhibits an antibacterial activity in a living body without affecting the intestinal bacterial colonies.
  • cephalosporin derivative of the invention may be useful in the same field as the conventional cephalosporin antibiotics since the cephalosporin derivative is transformed into a cephalosporin antibiotic in a living body.
  • the cephalosporin derivative of the invention may be used singly as an antibacterial drug.
  • the cephalosporin derivative of the invention may be used as an active ingredient of a pharmaceutical composition.
  • the pharmaceutical composition may contain a pharmaceutically acceptable carrier, diluent or adjuvant as well as at least one cephalosporin derivative of the invention and may be used in a dosage unit form.
  • the composition may be administered orally or rectally or by injection.
  • the dosage form for oral administration may be tablet, capsule, powder, granule, pill, ampoule, or the like.
  • the pharmaceutical composition may contain filler, extender, binder, wetting agent, disintegrant, retarder of dissolution, accelerator of absorption, adhesive carrier and/or lubricant, for example, starch, mannitol, silicic acid, cellulose derivative, gelatin, alginate, glycerol, agar, calcium carbonate, sodium hydrogen carbonate, paraffin, quaternary ammonium compound, glycerol monostearate, kaolin, bentonite, talc, potassium stearate, magnesium stearate, polyethylene glycol, and the like.
  • filler for example, starch, mannitol, silicic acid, cellulose derivative, gelatin, alginate, glycerol, agar, calcium carbonate, sodium hydrogen carbonate, paraffin, quaternary ammonium compound, glycerol monostearate, kaolin, bentonite, talc, potassium stearate, magnesium stearate, polyethylene glycol, and the like.
  • composition may be in the form of pharmaceutically acceptable emulsion, solution, suspension, or the like.
  • a suppository containing the cephalosporin derivative of the invention as an active ingredient may contain polyethylene glycol and/or fatty acid or ester thereof.
  • a syrup or elixir may contain an inert diluent such as water and paraffin and may be used as a liquid composition suitable for oral administration. These compositions may contain an adjuvant such as wetting agent, edulcorant and seasoning agent.
  • the composition for injection may be a sterilized aqueous or nonaqueous solution, suspension or emulsion and may contain, for example, propylene glycol, polyethylene glycol, olive oil, and the like.
  • composition may contain 0.01 to 99.5% by weight, preferably 0.1 to 90% by weight of the cephalosporin derivative of the invention as an active ingredient.
  • the cephalosporin derivative of the invention may be useful for the same use as the conventional cephalosporin antibiotics and effective in treating an infectious disease due to bacteria.
  • the dose may depend on the degree of the infection and the state of the patient, and generally the dose of 0.1 to 10 g may be administered to an adult patient per one day, divided into several times.
  • Ultraviolet absorption band U.V.
  • nm CH 3 CN
  • Each of the cephalosporin derivatives of the invention prepared in Examples 1 to 4 was dispersed in a physiological saline solution.
  • the dispersion was administered to ICR-JCL mice orally by a stomach sonde or intraperitoneally by injection at a predetermined amount.
  • LD 50 value was obtained from the cumulative mortality of the treated mice by applying the data to the Litchfield-Wilcoxon's graphycal method. All cephalosporin derivatives of the invention gave LD 50 value of more than 10 g/kg in both oral and intraperitoneal administrations.
  • the LD 50 value of cephalotin sodium (a conventional cephalosporin antibiotic) is about 5 g/kg.
  • Each of the cephalosporin derivatives of the invention prepared in Examples 1 to 4 was orally administered to mice (one group consisting of five female ICR mice of 6-week-old) for two consecutive days at a dose of 500 mg/kg/day.
  • feces of each mouse was collected and diluted with an anaerobic diluent (phosphoric buffer solution) of 100 times by volume and the diluted feces was ground.
  • anaerobic diluent phosphoric buffer solution
  • 0.1 ml of the diluted and ground feces was smeared on each culture medium shown in Table 1 and cultured aerobically or anaerobically (according to the anaerobic glove box method) under each condition shown in Table 1 and the number of each bacterium shown in Table 1 was counted.
  • Each bacterial strain was inoculated into the Mueller-Hinton's culture medium and cultured at 37° C. for 18 to 48 hours.
  • the cultured medium was diluted so as to contain 1 ⁇ 10 6 cells of the bacteria per one ml, and the obtained medium was used as the bacterial specimen.
  • Agar plates were prepared by adding one part by weight of each solution of the cephalosporin derivative of the invention at a predetermined concentration to nine parts by weight of Mueller-Hinton's culture medium.
  • a loopful amount of the bacterial specimen prepared above was smeared to make a streak of about 2 cm on each agar plate prepared above and cultured at 37° C. for 18 to 24 hours.
  • MIC minimum concentration for completely inhibiting proliferation of the bacteria
  • cephalosporin derivative of the invention was examined in the following experiment in order to prove that the cephalosporin derivative is activated in a living body.
  • a rat liver homogenate (S-9, manufactured by Oriental Yeast Company, Japan) was used in the following composition per 1 ml (hereinafter referred to as S-9 mix).
  • Staphylococcus aureus IAM 1011 was inoculated into a Mueller-Hinton's culture medium and cultured at 37° C. for 18 hours.
  • the culture medium was adjusted to a cell concentration of 1 ⁇ 10 8 per 1 ml and mixed with 50 times by volume of Mueller-Hinton's agar culture medium to obtain an agar plate.
  • a penicillin cup of 8 mm in diameter was placed on the agar plate prepared above, and into the cup 0.1 ml of the mixture containing the cephalosporin derivative prepared above was introduced and allowed to stand at 4° C. for 2 hours, and then cultured at 37° C. for 18 hours to measure the diameter of a circle in which the proliferation of bacteria was inhibited (proliferation-inhibiting circle).
  • the results are shown in Table 4.
  • the proliferation-inhibiting index is shown in the ratio (%) of the diameter of the proliferation-inhibiting circle obtained by using each of the cephalosporin derivatives of the invention to that obtained by using each of the starting compound in preparing each of the cephalosporin derivatives of the invention.
  • the cephalosporin derivative of the invention is activated by the action of an enzyme in a living body to recover the antibacterial activity, although the cephalosporin derivative of the invention per se shows a low antibacterial activity in the absence of an activating enzyme.
  • Escherichia coli IFO 12734 (1.4 ⁇ 10 8 cells) was inoculated intraperitoneally to ddY-SPF mice (a group consisting of 20 mice).
  • ddY-SPF mice a group consisting of 20 mice.
  • each of the cephalosporin derivatives of the invention prepared in Examples 1 to 4 was administered orally at a dose of 500 mg/kg, and the mortality of the mice due to infection was observed for 7 days. More than 35% of the mice administered with the cephalosporin derivative of the invention survived even on the 7th day after the infection, although all mice without administration of the cephalosporin derivative of the invention were dead on 2nd day after infection.
  • cephalosporin derivative of the invention is effective for oral administration against an infectious disease.
  • cephalosporin derivative of the invention and lactose was mixed and then an aqueous solution of hydroxypropylcellulose was admixed, and the mixture was kneaded, dried and pulverized. Then magnesium stearate preliminarily dispersed into starch was admixed and the mixture was tabletted by the conventional method.
  • cephalosporin derivative of the invention starch and lactose were mixed, and an aqueous solution of hydroxypropylcellulose was then admixed, and the mixture was dried and pulverized.
  • the pulverized material was sifted by 12 to 48 mesh sieves to obtain a granule.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US06/419,076 1981-09-18 1982-09-16 Cephalosporin derivative and pharmaceutical composition containing the derivative Expired - Lifetime US4446137A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP56147578A JPS5849386A (ja) 1981-09-18 1981-09-18 セフアロスポリン誘導体及び該誘導体を含有する医薬
JP56-147578 1981-09-18

Publications (1)

Publication Number Publication Date
US4446137A true US4446137A (en) 1984-05-01

Family

ID=15433520

Family Applications (1)

Application Number Title Priority Date Filing Date
US06/419,076 Expired - Lifetime US4446137A (en) 1981-09-18 1982-09-16 Cephalosporin derivative and pharmaceutical composition containing the derivative

Country Status (3)

Country Link
US (1) US4446137A (ja)
JP (1) JPS5849386A (ja)
ZA (1) ZA826823B (ja)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3635953A (en) * 1968-09-16 1972-01-18 American Home Prod 2-amidopenicillins and methods for their preparation
US3641015A (en) * 1969-01-17 1972-02-08 American Cyanamid Co 7 - (phenylacetylamino)cephalosporin carboxamides and 7 - (thiophene - 2-acetylamino) cephalosporin carboxamides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3635953A (en) * 1968-09-16 1972-01-18 American Home Prod 2-amidopenicillins and methods for their preparation
US3641015A (en) * 1969-01-17 1972-02-08 American Cyanamid Co 7 - (phenylacetylamino)cephalosporin carboxamides and 7 - (thiophene - 2-acetylamino) cephalosporin carboxamides

Also Published As

Publication number Publication date
JPS611076B2 (ja) 1986-01-13
JPS5849386A (ja) 1983-03-23
ZA826823B (en) 1983-07-27

Similar Documents

Publication Publication Date Title
SK61684A3 (en) D-2-aminoacyl-3-(z)-propenyl cephalosporine derivatives, a method of preparation and pharmaceutical compositions containing the same
US4918068A (en) Cephem compounds
US4540689A (en) Penicillin derivative
US4439434A (en) Cephalosporin derivative and pharmaceutical composition containing the derivative
US4496574A (en) Penicillin derivative
US4446137A (en) Cephalosporin derivative and pharmaceutical composition containing the derivative
US4496561A (en) Cephalosporin derivative
EP0075452B1 (en) Cephalosporin derivatives
EP0113242B1 (en) Cephalosporin derivatives
EP0075451B1 (en) Cephalosporin derivatives
US4734409A (en) Cephalosporin derivative, process for producing the same and pharmaceutical composition containing the same
US4681877A (en) Pivaloyloxymethyl 7-β-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-(2-amino-1,3-thiadiazolyl-5-thiomethyl)-3-cepheme-4-carboxylate and pharmaceutical composition containing the same
EP0113245B1 (en) Cephalosporin derivatives
JPH0160010B2 (ja)
JPH0160034B2 (ja)
DE3129158A1 (de) 1-dethia-1-oxa-3-cephem-4-carbonsaeure-verbindungen, verfahren zu ihrer herstellung und arzneimittel
JP4730879B2 (ja) キガマイシノン類及びその製造方法、並びに、該キガマイシノン類を含む薬用組成物
JPH0234357B2 (ja) Sefuarosuhorinjudotaioyobigaijudotaioganjusuruyakuzai
JPS6236386A (ja) セフアロスポリン誘導体、その製造方法及び該誘導体を含有する医薬
JPH021836B2 (ja)
JPH0240071B2 (ja) Sefuarosuhorinjudotaioyobigaijudotaioganjusuruyakuzai
JPH0235759B2 (ja) Sefuarosuhorinjudotaioyobigaijudotaioganjusuruyakuzai

Legal Events

Date Code Title Description
AS Assignment

Owner name: KUREHA KAGAKU KOGYO KABUSHIKI KAISHA, 9-11 HORIDOM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:MUTO, SHIGEAKI;NIIMURA, KOUICHI;ANDO, TAKAO;AND OTHERS;REEL/FRAME:004089/0195

Effective date: 19820901

STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12